Craniofacial abnormalities constitute up to one third of human congenital birth defects. The majority of these abnormalities arise due to defects in neural crest cell development. Neural crest cells are a migratory stem and progenitor cell population that generates most of the tissues in the head and face. Therefore it is essential to understand both the intrinsic and extrinsic mechanisms regulating neural crest cell development during embryogenesis. In the first part of this proposal we have developed a zebrafish model of Treacher Collins syndrome (TCS), which is a rare autosomal dominant human craniofacial disorder. TCS arises due to mutations in the gene TCOF1, which disrupts neural crest cell formation and proliferation. This zebrafish model enables us to investigate the developmental basis of an intrinsic neural crest cell defect and provides novel avenues for rescuing and preventing TCS. In the second part of this proposal we use an END generated mouse model of craniofacial abnormality to investigate and characterize the extrinsic patterning of neural crest cells. The combination of mouse and zebrafish approaches described in this proposal will help elucidate the mechanisms regulating neural crest cell development which will further our understanding of the origins and etiology of congenital craniofacial malformations. The major goals of this project are to use zebrafish and mice as model organisms to determine mechanisms by which facial tissues are formed and to uncover avenues for rescue and repair of a specific congenital craniofacial birth defect.